One key molecular abnormality of basal cell carcinoma (BCC) carcinogenesis is inappropriate activation of the hedgehog (HH) signaling pathway. This developmental pathway has a role in embryonic patterning and hair follicle development. In adult cells, genes responsible for cell proliferation, growth, and invasion are activated when the HH pathway is on. BCC tumors have an overactive HH signaling pathway that occurs often by mutational inactivation of the tumor suppressor Patched1 (PTCH1) gene. PTCH1 protein is a transmembrane receptor for HH ligands, and is a key inhibitor of HH signaling. PTCH1 inhibits HH target genes by repressing the function of SMOOTHENED (SMO) rendering downstream Gli transcription factors inactive. The HH ligands bind to the PTCH1 receptor, thus relieving inhibition of SMO and activating GLI transcription factors. Many BCC tumors have inactivating mutations in the PTCH1 gene that cause SMO signaling to be constitutively activated. GLI transcription factors are then continuously active and increase the expression of HH target genes. A biomarker for the HH pathway is GLI1 mRNA levels. BCC tumors have increased GUI levels, and molecularly targeted drugs against BCC have focused on antagonizing SMO as assessed by reduction of GUI mRNA. One such example is cyclopamine, a plant alkaloid that inhibits Smo. Model systems (in vitro and in vivo) showed that cyclopamine effectively inhibited BCGs, but systemic use of cyclopamine showed severe side effects that would preclude its use. SMO antagonists are efficacious vs. locally advanced and metastatic BCC tumors (von Hoff, NEJM 2009), but they cause significant side effects such as taste loss and myalgia that would prevent their long-term use.
Subjects who inherit one defective copy of PTCH1 have the Basal Cell Nevus Syndrome (BONS) also known as Gorlin Syndrome, a rare multi-system disease whose hallmark is the development of dozens to hundreds of BCCs. BONS is an orphan disease with a prevalence of 1 case per 56,000-164,000 in the population with no effective and tolerable treatments. Consequently, drugs that treat or prevent BCC tumors are of interest for subjects with BONS.
Topical triazole-triazolone compositions are of interest for various clinical purposes, including use in treating or preventing the development of BCCs in two clinical populations: i) patients with hereditary BCC tumors, e.g., patients with Basal Cell Nevus Syndrome; and ii) patients in the general population with sporadic BCC tumors. In the United States, BCC is the most common cancer diagnosed with 1 million new cases per year. Though BCCs are rarely fatal, their high incidence and frequent recurrence in affected individuals can cause significant morbidity. Currently, the incidence of skin cancer is increasing yearly and treatment of skin cancer imposes a huge burden on national health services. Currently, there is no effective therapy for BCC prevention as sunscreens have not been shown to reduce BCC development in a randomized controlled trial. Accordingly, topical triazole-triazolone compositions and methods of using the same are of significant interest.